In theory, drugs for the treatment of cancer and tumors should have the capability to accomplish several key goals. First, the drug generally should be able to reach the area of the body where the disease/tumor resides (e.g., brain, lung, breast). The drug should preferably be able to “target” diseased cells (i.e., differentiate between normal cells and diseased cells). The drug should also generally be able to be to transverse various cellular membranes and/or to be “uptaken” by the diseased cell in order to interact with the constituents of that cell. The drug should preferably be able to “recognize” a critical disease related entity (DNA/RNA/Protein) and be capable of binding to it in some fashion (i.e. anti-sense, nucleotide base π-stacking intercalation, triplex formation). Finally, the drug should terminate the disease entity's ability to function (grow) either by inhibition or destruction. The majority of cancer drugs currently in use fail, to a significant degree, with respect to one or more of the attributes listed above. In addition, most cancer drugs currently in use are effective only against very specific types of cancer (i.e. “taxol” for ovarian cancer; “cis-platin” against lung, testicular, and neck tumors) and thus have limited applicability. A single drug which has applicability against a wide variety of cancerous cell lines would be a significant addition to the current arsenal of chemotherapeutic drugs.
Through the use of mutant cell lines which did not require polyamines as well and specific enzyme inhibitors, the metabolic cycle for polyamines has been studied. This has led to several important findings; 1) polyamine levels are much higher in rapidly growing cells than in normally growing cells; 2) polyamines are required for cell growth (i.e., when cells are starved of polyamines, growth stops, but growth resumes to normal when exogenous polyamines are added to the cell culture media); 3) when needed, cells can uptake exogenous polyamines to sustain growth; 4) structural analogues of the natural polyamines can also be taken up by cells from the exogenous media to approximately the same degree as the natural polyamines but the structural analogues are not metabolized within the cell; and 5) when polyamine levels become too high in the cell, polyamines are disposed of either by metabolic breakdown of the polyamines or excretion from the cell.
It has been suggested by several researchers that the polyamine metabolic system might be utilized in conjunction with chemotherapeutic protocols. Probably the most intriguing aspect of this suggestion as it relates to drug design is evidenced by recently reported research which demonstrated that: 1) many diseased cells, particularly cancer cells, have higher intracellular concentrations of the natural polyamines than do normal cells; 2) cells which have higher intracellular concentrations of the natural polyamines take up polyamines in the exogenous media to a much higher degree; and 3) some structural analogues of natural polyamines are taken up by cells from the exogenous media to approximately the same degree as the natural polyamines but the structural analogues are not metabolized within the cell. Taking these factors into consideration suggests that polyamines could represent a motif which might be utilized to simultaneously provide a cellular uptake vehicle as well as a cancer cell targeting capability.